P-substituted-benzenesulphonyl biguanides and methods for their preparation



Patented Sept. 15, 1942 P-SUBSTITUTED BENZENESULP-HONYL BIGUANIDES ANDMETHODS FOR THEIR PREPARATION Philip Stanley Winnek, Riverside, Conn,as-

signor to American Cyanamid Company, New York, N. Y., a corporation ofMaine No Drawing. Application February 24, 1941, Serial No. 380,336

14 Claims.

The present invention relates to anew class of chemical compounds andmethods for their preparation. More particularly it relates to psubstituted-benzenesulphonyl biguanides and methods for theirpreparation.

This new class of compounds are'those represented by the followinggeneral formula:

in which X represents an amino or a substituted amino radical, such asalkylamino, aralkylamino, arylamino, hydroxylamino, aldose amino, sodiumiormaldehyde sulphoxalate amino,-and the like, or a radical which can bereduced to an amino group, including nitro and azo radicals andacylamino radicals which can be converted to an amino group byhydrolysis, and B represents biguanide or a substituted biguanideradical. The invention also includes acid salts of the compoundsrepresented by the above general formula.

The compounds of this invention are useful as intermediates for theproduction of azo dyes and pharmaceuticals. Some of the compounds may beuseiulas chemotherapeutic agents themselves since it is known thatsulphanilyl guanidine does Eximrtn 1 p-Nitrobenzenesidphonyl biouanide/NH mN-0=NH parts oi! biguanide are suspended in 125 parts or acetone.The mixture is cooled to 15 C. and 23 parts of p-nitrobenzenesulphonylchloride are added gradually with vigorous stirring and with thetemperature kept between 15 and 20? C. The mixture is stirred for onehour. The yellow precipitate of crude p-nitrobenzenesulphonyl biguanidewhich forms is then filtered oil! and purified by crystallization fromacetic acid.

- The product so obtained can readily be conpossess therapeuticactivity, and the compounds 01 the present invention have some similarphysical and chemical properties.

In general the compounds of the present invention may be prepared byreacting ap-X benzenesulphonyl halide with a biguanide having an active-NH: group, in which X represents an acylamino group, such asacetylamino, which can be hydrolyzed to an amino group. or a nitro orazo group which can be reduced to an amino group, and it is thereforeapparent that X may be an amino group produced by either of the abovedescribed processes.

The methods for preparation of the compounds of this invention will bespecifically illustrated in the following examples. It should beunderstood, however, that the exampies are merely illustrative of thepreferred methods of preparing representative compounds oi the class andare not intended to limit the scope oi. the invention. The parts are byweight except in the case of liquidswhich are expressed in correspondingparts by volume.

verted to the p-amino compound by iron reduction. I

EXAMPLE 2 N-acetylsuZphanil1/Z biguam'de cmc 0HNOsomHc NH 4 The almostwhite precipitate of crude N-acetylsulphanilyl biguanide which forms isfiltered on and purified by crystallization from hot water.

EXAMPLE 8 Sulpnanilyl Oiguamde the solution is boiled ten minutes. 200parts of ice are then added and the resulting cold solution isneutralized with sodiumhydroxide-solution;

The crude sulphanilyl biguanide which separates is filtered oil andpurified by crystallization from- Exams: 4 N acetulsulphanilylbuti lbiguamde NE NH Ill-parts of butyl biguanide. hydrochloride are suspendedin 60 parts of acetone and 5 parts of sodium hydroxide dissolved in 15parts of water are added. The mixture is cooled to 15 C. and 13 partsoi'acetylsulphanilyl chloride are added gradually with stirring, keepingthe temperature between 15 and 20 C. Stirring is continued for one hourat room temperature and the mixture is then warmed to. 45 C. for fifteenminutes.

It is then cooled and ice is added. The N -acetylsulphanilylbutylbiguanide separates as a gummy precipitate which on standing with waterturns to a light yellow solid.

Enmru: 5 Sulphanilyl butul biguam'de 5.5 parts of N -acetylsulphanilylbutyl biguanide are suspended in 15 parts of 4 N hydrochloric acid andthe mixture is heated to boiling. The solid material soon dissolves andthe solution is boiled gently for five minutes. It is then diluted withan equal volume of ice and the cold solution is stirred for fifteenminutes with decolorizing charcoal. It is filtered and the filtrateneutralized in the cold with sodium hydroxide. The crude sulphanilylbutyl biguanide separates as a tarry material which on standing turns toa solid. It is purified by crystallization from methanol usingdecolorizing charcoal to remove color. The final product is a whitecrystalline material.

Exam'na 6 I N-acetylsulphanilyl dimethyl biguanide NE NH cmc oaN-Osomm-NH- -Nwm),

summit: dimethyl biguanide NE NH nmO-soma-a i-rrg- -mcnm 9 parts of N-acetylsulphanilyl dimethyl bigua nide are suspended in 21 parts or 4 Nhydrochloric acid and boiled gently for five minutes. The resultingsolution is diluted with an equal volume of ice and stirred for one-halfhour with decolorizing charcoal. It is filtered and the filtrateneutralized in the cold with sodium hydroxide solution. The sulphanilyldimethyl biguanide separates as a white solid. It is purified bycrystallization lution.

} EXAMPLE 8 N -acetylszdphanilyl-o-tolyl biouanide 2 parts of o-tolylbiguanide are suspended in 10" parts of acetone and 0.6 part of sodiumhydroxide dissolved in 2 parts of water are added. The mixture is cooledto C. and 2.5 parts of acetylsulphanilyl chloride are added graduallywith from an alcohol-water stirring and with the temperature keptbetween 15 and 20 C. The mixture is stirred for one hour at roomtemperature and is then warmed slightly until most of the acetone hasevaporated. Water is then added and the mixture is neutralized withacetic acid. The N -acetylsulphanilyl-o-tolyl biguanide separates as atarry material which turns solid on standingin the cold with water.

EXAMPLE- 9 Sulphanilyl-o-tolul biauanide tralized with sodium hydyroxidesolution. The

sulphanilyl-o-tolyl biguanide separates as a tarry, material whichsolidifies on standing in the cold. It is purified by crystallizationfrom an alcoholwater solution using decolorizlng charcoal to removeimpurities.

EXAMPLE '10 N -Acet ulsulphanilyl biguanylntorpholine NE NH CHI-CH2 ll gcaloouN SOiNH-C-NH- N\ o GHQ-CH! 5.2 parts of biguanyl morpholinehydrochloride are suspended in 30 parts of acetone and 2.5 parts ofsodiumhydroxide dissolved in 7 parts of water are added. The mixture iscooled to 20 C. and 6.5 parts of acetylsulphanilyl chloride are addedgradually with stirring and with the temperature kept between 18 and 23C. The mixture is stirred for five hours and parts of water are addedand the mixture is neutralized with acetic acid and allowed to stand inthe ice box rorsixteen hours. The N acetylsulphonilyl biguanylmorpholine separates as a yellow solid. It may be purified bycrystallization from hot water using decolorizing charcoal to removeimpurities.

EXAMPLE l1 Sulphanilyl biguanyl morpholine ND NE CHr-CH! mi "lites. Theresulting solution is diluted with an equal volume oi ice and the coldsolution is I substantially one molecular proportion of the pounds maybe used, including those such as propionyl, butyryl, deconyl, benzoyl,furoyl, nicotinyl, and the like. Similarly, instead ofpacetylaminobenzenesulphonyl chloride the correspondingp-acetylaminobenzenesulphonyl bromide or other halide may be used.

In the foregoing examples certain specific alkyl, aryl, and heterocyclicsubstituted biguanides have been used in carrying out the reactions.These substituted blguanides may be replaced by any other substitutedbiguanide containing an aliphatic, alicyclic, aliphatic heterocyclic,aromatic, heterocyclic, or other substituent group as long as theblsuauide also contains an active -NH: group which will react withsulphonyl chloride to split oi! HCl.

Arylamino, allrylamino, aralkylamino, alicyclicamino, monoaldoseamino.hydroxylamino, sodium formaldehyde sulphoxalate amino, and similarderivatives-of the p-amino compounds illustrated in the examples may beprepared by known methods, such as by the use of an acyl, allcyl.arallayl halide, a monoaldose sugar such as for example glucose, etc.

The structural formulae given in the examples are probably correct:however, this has not definitely been proven and the invention is not tobe limited to the compounds having those structural formulae for it isentire y Possible that the biguanide radical may couple to the SO:radical in a manner different from that illustrated. As for example,linkages may be as follows:

phosphates, chlorates, and the like. may be prepared by adding thep-amino compound to a relatively strong aqueous solution of the acid.

A salt produced by the reaction. may be very conveniently recovered bydiluting the aqueous solution with an organic solvent such as acetoneand recovering the resulting precipitate by filtration. The salts of thewater soluble organic acids. such as for example, acetic, lactic,citric,

and the like, may be prepared as described in the process above. Anothersuitable method for preparing the salts comprises a method in whichphonyl biguanide hydrochloride, preferably in the form of an aqueoussolution, is reacted with sodium salt of an organic acid, for example.sodium phthalate, also preferably in aqueous solution and the acid saltseparated from the sodium chloride.

It is readily seen, therefore, that the present invention relates to andincludes any inorganic acid salt. Similarly this invention includes a yorganic acid salt oi p-aminobenzenesulphonyl biguanlde including thesaturated and unsaturated hydroxy, halogenated or other substitutedacids of the aliphatic, ,alicyclic, aromatic, and heterocyclic series.Preferably the salts are those produced from relatively non-toxicorganic acids or those having some bactericidal or other therapeuticproperty, including acids such as acetic, salicyclic, mandelic, lactic,and the like.

The above description and examples are inrepresented by the followinggeneral formula and inorganic and carboxylic acid salts thereof:

inwhichxisa amino group and radicals reducible to an amino group, and Brepresents a biguanide radical.

2. The compounds represented bythe iollowing general formula:

3. The compounds represented by the following general formula:

in which Z represents a group capable of being reduced to an amino groupand B represents a biguanide radical.

4. The compounds represented by the following generalformula:

in which B represents a biguanide radical.

6. The compounds represented by the following general formula:

MOI-Own:

n-nQsom a relatively water insoluble organic acid. such as in which 8represents a biguanide radical.

member of the group consisting of amine radicals, radicals hydrolyzableto an 7. The compound p-riitrobenzenesulphonyl biguanide.

' 8. The compound N -acetyisu1phani1y1 biguanide.

9. The compound sulphanilyi biguanide.

10. The process which comprises reacting a biguanide with ap-nitrobenzenesulphonyl halide and subjecting the reaction product to areduction treatment converting the nitro group to an amino group.

11. The process which comprises reacting a biguanide with a.p-acetylaminobenzenesuiphonyl halide and subjecting the reaction productto a hydrolysis treatment to remove the acetyl group.

12. The process of producing p'-a.minobenzenesulphonyl biguanide whichcomprises reacting biguanide with p ecetylaminobenzenesulphonyl chlorideand hydroiyzing the resulting acetyi compound to the amino compound.

13. The process of producing p-aminobenzenesulphonyi biguanide whichcomprises reacting biguanide with p-nitro'benzenesul-phonyi chloride andreducing the resulting nitro compound to the amino compound.

14. The process of producing p-substituted =benzenesulphonyibiguanidecompounds which comprises reacting a p-X-benzene-SOz-halogen with abiguanide in which X is a member of the group consisting of radicalshydrolyza-ble to an amino group and radicals reducible to an aminogroup.

PHILIP STANLEY WINNE'K.

